ABSTRACT It is estimated that as many as 5.5 million Americans age 65 and older may have Alzheimer?s disease (AD). AD is currently ranked as the sixth leading cause of death in the United States and accounts for 60% to 70% of cases of dementia. AD is an irreversible, progressive neurodegenerative disease that slowly destroys memory and thinking skills, and eventually the ability to carry out the simplest tasks. There is no cure and there is no early detection available. The blood brain barrier (BBB) presents a barrier to delivery of therapeutic compounds such as growth factors that might be used to treat AD. Ultrasound (US) + microbubbles (MB) as cavitation nuclei have been used to safely and reversibly open the BBB in AD patients (using Definity MB, originally developed by a collaborator on this grant). MB-based ultrasound contrast agents (USCA) are used to improve the accuracy of ultrasound (US). Definity (perflutren, developed by our collaborator) is the world's leading USCA, At Microvascular Therapeutics (MVT) has developed a new, neutral electrostatically, improved perflutren (MVT- 100) USCA (U.S. Patent No. 9,801,959). MVT-100 MB are roughly 1-2 microns in size. Sub-micron sized acoustically active materials, especially phase change nanodroplets (ND, ~ 100-200nm), may more easily penetrate the blood brain barrier (BBB) and have enhanced therapeutic and diagnostic properties for AD. MVT has produced phase change sub-micron sized ND contrast agents that can penetrate cells. We have also developed technology for incorporating payloads of proteins and nucleotides into ND. Moreover, we have designed and synthesized small molecules that are chemical derivatives of the known clinically used PET agents namely AMYViD, NeuraCeq and Vizamyl. NDs conjugated with these derivatives recognize the Tau and ?- Amyloid (A?) protein aggregates in vitro and preliminary results demonstrate a disruption of protein aggregates upon US activation in the in vitro assay as measured by the release of Thioflavin dye present in the aggregates. Our goals in this SBIR Phase I are 1) to show that opening of the BBB first with US + MB allows NDs to pass through the BBB and that 2) a second session of imaging/activation performed after the NDs have entered the brain tissue allows the NDs to interact with A? aggregates or Tau neurofibrillary tangles and that 3) upon cavitation of these targeted NDs, the aggregates are disrupted. Our goals are to translate the technology in vivo in animal models of AD and evaluate their efficacy as a first diagnostic and validity and safety as a theranostic tool for AD patients. This project is poised to move forward rapidly based on the MVT-100 platform and to lead to the rapid development of a detection and potential treatment modality for AD patients. Ultimately our goal is to develop this as a platform theranostic technology for diagnosis of AD as well as for treatment and delivery of therapeutic materials including growth factors and nucleotide-based therapeutics.